NO318023B1 - Precursor device containing a reagent system for determining the presence or amount of analyte in a sample - Google Patents

Precursor device containing a reagent system for determining the presence or amount of analyte in a sample Download PDF

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NO318023B1
NO318023B1 NO19971012A NO971012A NO318023B1 NO 318023 B1 NO318023 B1 NO 318023B1 NO 19971012 A NO19971012 A NO 19971012A NO 971012 A NO971012 A NO 971012A NO 318023 B1 NO318023 B1 NO 318023B1
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analyte
sample
enzymes
reagent system
oxidase
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NO971012L (en
NO971012D0 (en
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Yeung Siu Yu
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Lifescan Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]

Abstract

A dye coupled compound is provided for use in a test device containing a reagent system for detecting the presence or quantity of an analyte in a sample. The reagent system comprises one or more enzymes which, in the presence of the analyte, produce an oxidising agent in quantities indicative of the quantity of analyte in the sample. The compound of choice is metaÄ3-methyl 2-benzothiazolinonehydrozoneÜN-sulfonyl benzenesulfonate monosodium.

Description

Foreliggende oppfinnelse angår en forsøksanordning inneholdende et reagenssystem for bestemmelse av nærvær eller mengde analytt i en prøve. Reagenssystemet innbefatter enzymer for å danne et oksydasjonsmiddel i mengder som er indikative for mengdene analytt i prøven, og et fargepar som danner en kromofor ved oksydasjon med oksydasjonsmiddelet. The present invention relates to a test device containing a reagent system for determining the presence or amount of analyte in a sample. The reagent system includes enzymes to form an oxidizing agent in amounts indicative of the amounts of analyte in the sample, and a dye pair that forms a chromophore upon oxidation with the oxidizing agent.

Kvantifisering av kjemiske og biokjemiske komponenter i fargede vanndige fluider, spesielt fargede biologiske fluider så som helblod og urin og biologiske fluidderivater så som serum og plasma, har fått en stadig økende betydning. Viktige anvendelsesområder er innen medisinsk diagnose og behandling og ved kvantifisering av eksponering til terapeutiske legemidler, intoksikanter, skadelige kjemikalier og lignende. I visse tilfeller er mengdene av materialer som skal bestemmes enten så små - i størrelsesorden ett milligram elter mindre pr. desiliter - eller så vanskelig å bestemme nøyaktig at apparatet som anvendes er komplisert og kan kun anvendes av faglært laboratoriepersonell. I dette tilfellet, er resultatene ofte ikke tilgjengelige før etter noen timer eller døgn etter prøvetakingen. I andre tilfeller er det ofte viktig at legoperatører kan utføre testen rutinemessig raskt og reproduserbart utenfor en laboratorieoppstilling med rask eller umiddelbar informasjonsvisning. Quantification of chemical and biochemical components in colored aqueous fluids, especially colored biological fluids such as whole blood and urine and biological fluid derivatives such as serum and plasma, has gained an ever-increasing importance. Important areas of application are in medical diagnosis and treatment and when quantifying exposure to therapeutic drugs, intoxicants, harmful chemicals and the like. In certain cases, the quantities of materials to be determined are either so small - on the order of one milligram or less per deciliters - or so difficult to determine precisely that the apparatus used is complicated and can only be used by trained laboratory personnel. In this case, the results are often not available until a few hours or days after the sampling. In other cases, it is often important that medical operators can routinely perform the test quickly and reproducibly outside of a laboratory setup with quick or immediate information display.

En vanlig medisinsk test er måling av blodglukosenivåer hos diabetikere. Nåværende teknikk medfører at diabetespasientene må måle sitt blodglukosenivå fra to ul syv ganger pr. dag, avhengig av typen og alvorligheten i deres spesielle tilfelle. Basert på det observerte mønsteret av målte glukosenivåer, kan pasienten og legen sammen gjøre justeringer av diett, trening og insulininntak for bedre å kunne handtere lidelsen. Denne informasjonen bør helt klart være tilgjengelig for pasienten umiddelbart. A common medical test is the measurement of blood glucose levels in diabetics. Current technology means that diabetic patients must measure their blood glucose level from two ul seven times per day. day, depending on the type and severity of their particular case. Based on the observed pattern of measured glucose levels, the patient and doctor can together make adjustments to diet, exercise and insulin intake to better manage the condition. This information should clearly be available to the patient immediately.

Det er kjent mange blodglukosetestmetoder og testartikler, men alle disse har forskjellige begrensninger. En stor forbedring er beskrevet og vist i US-PS 4.935.346, 5.049.487, 5.059.394 og 5.179.005 til R. Phillips et al. og overdratt til samme søker som foreliggende søknad. Many blood glucose test methods and test articles are known, but all of these have different limitations. A major improvement is described and shown in US-PS 4,935,346, 5,049,487, 5,059,394 and 5,179,005 to R. Phillips et al. and transferred to the same applicant as the present application.

Fremgangsmåten beskrevet i disse patentene medfører å ta en reflektansavlesning fra en overflate til en inert porøs matriks impregnert med en reagens som vil samvirke med analytten og danne et lysabsorberende reaksjonsprodukt når fluidet som skal analyseres påføres en annen overflate og migrerer gjennom matriksen til overflaten som avleses. Reagensen innbefatter glukoseoksydase, et enzym som forbruker glukose i prøven og danner hydrogenperoksid, som i nærvær av et annet enzym, pepperrotperoksydase oksyderer et fargepar innbefattende 3-metyl-2-bensotiazolinon hydrazon hydroklorid (MBTH) og 3-dimetylaminbenzosyre (DMAB) og gir en blå farge. Det utføres deretter reflektansmålinger ved to separate bølgelengder. Konsentrasjonen av glukose i blodet blir bestemt basert på intensiteten til fargestoffet ved hjelp av et LED-spektro-fotometer. The method described in these patents entails taking a reflectance reading from a surface to an inert porous matrix impregnated with a reagent that will interact with the analyte and form a light-absorbing reaction product when the fluid to be analyzed is applied to another surface and migrates through the matrix to the surface being read. The reagent includes glucose oxidase, an enzyme that consumes glucose in the sample and forms hydrogen peroxide, which in the presence of another enzyme, horseradish peroxidase, oxidizes a dye pair including 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) and 3-dimethylamine benzoic acid (DMAB) to give a blue color. Reflectance measurements are then carried out at two separate wavelengths. The concentration of glucose in the blood is determined based on the intensity of the dye using an LED spectrophotometer.

Videre beskriver kjent teknikk EP A 0 248 312, en testanordning med enzym og fargedanner der forbindelsen er 2-hydrazono-4,6-dinitro-benzthiazoloner. Furthermore, known technique EP A 0 248 312 describes a test device with enzyme and color former in which the compound is 2-hydrazono-4,6-dinitro-benzthiazolones.

I vår patentsøknad U.S.S.N. 245.940, inngitt 19. mai, 1994, er det beskrevet et fargepar bestående av 3-metyl-2-benzotiazolinon hydrazon i fri fonn eller i syreform (MBTH) og 8-anilino-L-natfalensulfonat, i syre- eller saltform (ANS) som anvendes i stedet for MB TH-DM AB fargeparet som beskrevet over. MBTH-ANS fargeparet er mindre løslige ved oksidasjon og gir derved et mer stabilt endepunkt, med minimal fargesvekkelse, sammenlignet med det oksiderte MBTH-DMAB fargeparet. In our patent application U.S.S.N. 245,940, filed May 19, 1994, a dye pair consisting of 3-methyl-2-benzothiazolinone hydrazone in free or acid form (MBTH) and 8-anilino-L-naphthalene sulfonate, in acid or salt form (ANS) is described. which is used instead of the MB TH-DM AB color pair as described above. The MBTH-ANS dye pair is less soluble upon oxidation and thereby provides a more stable end point, with minimal color weakening, compared to the oxidized MBTH-DMAB dye pair.

Selv om disse tidligere systemene effektivt har vært brukt for å fremstille anvendelige testanordninger for bestemmelse av nærværet eller mengden av glukose, er flere ulemper notert. Testanordningene som benytter slike fargepar, er utformet både for hjemmebruk og for profesjonelt bruk og blir så sådann solgt av produsenter og distributører med det for øyet at brukeren vil anvende dem over en betydelig tids-periode, slik at de selvfølgelig må være effektive i hele denne tidsperioden. Dette behovet for en betydelig lagringstid har medført vanskeligheter med fremstilling av produkter som anvender MBTH som en av komponentene i et fargepar. Although these prior systems have been effectively used to produce useful test devices for determining the presence or amount of glucose, several disadvantages have been noted. The test devices that use such color pairs are designed both for home use and for professional use and are sold as such by manufacturers and distributors with the intention that the user will use them over a considerable period of time, so that of course they must be effective throughout this the time period. This need for a significant storage time has led to difficulties in the manufacture of products that use MBTH as one of the components in a color pair.

For det første er det funnet at stabiliteten til MBTH avtar med økende temperatur og alkalinitet. Den syrefrie formen av MBTH er meget utsatt for å sublimere bort. I et forsøk på å motvirke dette, er en foretrukket form syrehydratet av MBTH for eksempel 3-metyl-2-benzoriazolinon hydrazon hydroklorid. Dette hydratet er dessverre i seg selv ustabilt ved økende temperatur og dissosierer lett i syrefri MBTH og HC1 ved oppvarming. I tillegg til å ha lav stabilitet ved høy pH, vil effektiviteten av MBTH til oksidativt å reagere med sin koblingspartner sterkt avta med økende alkalinitet, slik at ved høy pH vil det dannes liten eller ingen farge fra fargeparet. Firstly, it has been found that the stability of MBTH decreases with increasing temperature and alkalinity. The acid-free form of MBTH is very prone to sublime away. In an attempt to counteract this, a preferred form is the acid hydrate of MBTH, for example 3-methyl-2-benzoriazolinone hydrazone hydrochloride. Unfortunately, this hydrate is inherently unstable at increasing temperature and easily dissociates into acid-free MBTH and HC1 when heated. In addition to having low stability at high pH, the efficiency of MBTH to oxidatively react with its coupling partner will greatly decrease with increasing alkalinity, so that at high pH little or no color will be formed from the dye pair.

I lys av disse forhold, må MBTH i praksis brukes i store overskudd og ved lav pH for å minimalisere effektene av ustabilitet og ineffektivitet. Ideelt ville en pH på mindre enn 2.0 være foretrukket i lys av lav sublimasjon og høy effektivitet for forbindelsen. For systemene som behandles her, kan det imidlertid ikke anvendes en slik ideell lav pH. Som beskrevet ovenfor, er reagenssystemene som anvendes avhengig av enzymer for å virke på substratanalytten og danne oksidasjonsreagenser i mengder som er indikative for mengdene av analytt som er tilstede i prøven som undersøkes. Den lave pH-en som ville være ideell med hensyn til MBTH reagensen, er fullstendig upassende for enzymer så som for eksempel glukoseoksidase og pepperrotperoksidase. Ved slik lav pH vil mange av de kommersielt tilgjengelige enzymene ha liten eller ingen aktivitet. Man har derfor vært tvunget til å anvende en moderat pH, f.eks. 4, og et stort overskudd av reagenser for å sikre testanordningenes effektivitet gjennom hele den nødvendige lagringstid. In light of these conditions, in practice, MBTH must be used in large excess and at low pH to minimize the effects of instability and inefficiency. Ideally, a pH of less than 2.0 would be preferred in view of low sublimation and high efficiency of the compound. However, for the systems treated here, such an ideally low pH cannot be used. As described above, the reagent systems used rely on enzymes to act on the substrate analyte and form oxidation reagents in amounts indicative of the amounts of analyte present in the sample under investigation. The low pH that would be ideal with regard to the MBTH reagent is completely inappropriate for enzymes such as glucose oxidase and horseradish peroxidase. At such a low pH, many of the commercially available enzymes will have little or no activity. One has therefore been forced to use a moderate pH, e.g. 4, and a large surplus of reagents to ensure the effectiveness of the test devices throughout the required storage time.

I henhold til læren ved foreliggende oppfinnelse, er det tilveiebragt en meget stabil komponent til et fargepar i en testanordning innbefattende enzymer. Komponenten, i motsetning til de som ble brukt i kjente anordninger, er istand til effektiv oksidativ kobling med en lang rekke koblingspartnere ved relativt høy pH hvilket er kompatibelt med høy enzymeffektivitet. According to the teachings of the present invention, there is provided a very stable component to a color pair in a test device including enzymes. The component, unlike those used in known devices, is capable of efficient oxidative coupling with a wide range of coupling partners at relatively high pH which is compatible with high enzyme efficiency.

Foreliggende oppfinnelse angår således en forsøksanordning inneholdende et reagenssystem for bestemmelse av nærværet eller mengden av en analytt i en prøve, hvor reagenssystemet innbefatter enzymer for å danne et oksydasjonsmiddel i mengder som er indikative for mengdene av. analytt i prøven, der The present invention thus relates to a test device containing a reagent system for determining the presence or amount of an analyte in a sample, where the reagent system includes enzymes to form an oxidizing agent in amounts that are indicative of the amounts of. analyte in the sample, there

reagenssystemet innbefatter et fargepar som danner en kromofor ved oksydasjon med oksydasjonsmidlet, kjennetegnet ved at fargeparet omfatter the reagent system includes a color pair that forms a chromophore upon oxidation with the oxidizing agent, characterized in that the color pair includes

meta[3-metyl 2-benzottazolinon hydrazon]N-sulfonyl benzensulfonat mononatrium. Figur 1 viser en perspektivskisse av en utføretsesform av en testanordning inneholdende en reaksjonspute, til hvilken væskeprøven som skal analyseres påføres. Figur 2 viser en perspektivskisse av en andre utføretsesform av anvendelsen av forsøks-anordningen i figur 1. meta[3-methyl 2-benzotazolinone hydrazone]N-sulfonyl benzenesulfonate monosodium. Figure 1 shows a perspective sketch of an embodiment of a test device containing a reaction pad, to which the liquid sample to be analyzed is applied. Figure 2 shows a perspective sketch of a second embodiment of the use of the experimental device in Figure 1.

Som beskrevet over, innbefatter oppfinnelsen en forsøksanordning inneholdende et reagenssystem for bestemmelse av nærværet eller mengden av en analytt i en væskeprøve. I figur 1 i en foretrukket utførelsesform av denne oppfinnelsen innbefatter testanordningen en porøs matriks 10, hvori det er innbefattet et kjemisk reagenssystem og som er festet til en bærer 12. Gjennom bæreren er det tilveiebragt en åpning 16 hvorved en væskeprøve kan påføres en prøvemottaksflate 17 til matriksen 10. Det kjemiske systemet er tilveiebragt for å reagere med enhver analytt som er tilstede i væskeprøven og resulterer i at testoverflaten 19 til matriksen manifisterer lysreflektans-egenskaper som indikerer mengden av analytt som er tilstede i væskeprøven. Testoverflaten kan avlese med det nakne øyet, men avleses fortrinnsvis ved bruk av en spektraofotometeranordning. Elementene i en slik anordning er vist skjematisk i figur 1 og innbefatter en lyskilde 18, så som en lysemitterende diode, for å rette lys med fortrinnsvis jevn bølgelengde på testoverflaten 19. Det er i tillegg tilveiebragt en lys-detektor 20 for å detektere reflektert lys fra overflaten 19 og danne et signal 22 som indikerer mengden av detektert lys, hvilket signal for eksempel kan behandles av en mikroprosessor i avlesningsapparatet for å beregne mengden av analytt i prøven. As described above, the invention includes a test device containing a reagent system for determining the presence or amount of an analyte in a liquid sample. In Figure 1 in a preferred embodiment of this invention, the test device includes a porous matrix 10, in which a chemical reagent system is included and which is attached to a carrier 12. An opening 16 is provided through the carrier through which a liquid sample can be applied to a sample receiving surface 17 to the matrix 10. The chemical system is provided to react with any analyte present in the liquid sample and results in the test surface 19 of the matrix manifesting light reflectance properties indicative of the amount of analyte present in the liquid sample. The test surface can be read with the naked eye, but is preferably read using a spectrophotometer device. The elements of such a device are shown schematically in Figure 1 and include a light source 18, such as a light-emitting diode, to direct light of preferably uniform wavelength onto the test surface 19. A light detector 20 is also provided to detect reflected light from the surface 19 and form a signal 22 indicating the amount of detected light, which signal can for example be processed by a microprocessor in the reading device to calculate the amount of analyte in the sample.

Slike systemer som beskrevet ovenfor er kjent og beskrevet i US-PS 4.935.346, 5.049.487,5.059.394 og 5.179.005. Slike systemer medfører at disse testanordningene også vil bli innført i et avlesningsapparat og deretter vil prøven, for eksempel blod, bli påført den prøvemottakende overflaten 17. Figur 2 representerer et alternativ til dette, hvor blodet først påføres den prøvemottagende overflaten 17 og deretter blir testoverflaten 19 presentert for apparatet for avlesning. I alle andre henseender er de nummererte elementene i figur 2 identiske til de i figur 1. Such systems as described above are known and described in US-PS 4,935,346, 5,049,487, 5,059,394 and 5,179,005. Such systems mean that these test devices will also be introduced into a reading device and then the sample, for example blood, will be applied to the sample receiving surface 17. Figure 2 represents an alternative to this, where the blood is first applied to the sample receiving surface 17 and then becomes the test surface 19 presented to the apparatus for reading. In all other respects, the numbered elements in Figure 2 are identical to those in Figure 1.

Reflektansegenskapene til testoverflaten varierer med analyttmengden i prøven ved operasjon av en serie kjemiske reaksjoner mellom analytten i væskeprøven og de kjemiske reagensene som er tilstede i den porøse matriksen. Spesielt innbefatter matriksen ett eller flere enzymer, som sammen med analyttbestanddelen, resulterer i dannelsen av hydrogenperoksid eller andre sterke oksidasjonsmidler. Et fargapar er innbefattet i matriksen, det vil si to forbindelser som er istand til å oksideres og danne en kromofor som absorberer lys ved spesifikke bølgelengder i forhold til mengden av kromofor som er tilstede. Oksidasjonsmidlet dannet ved den enzymkatalyserte reaksjonen, reagerer deretter med fargestoffprøven og danner kromoforen. The reflectance properties of the test surface vary with the amount of analyte in the sample by operation of a series of chemical reactions between the analyte in the liquid sample and the chemical reagents present in the porous matrix. In particular, the matrix includes one or more enzymes, which, together with the analyte component, result in the formation of hydrogen peroxide or other strong oxidizing agents. A color pair is included in the matrix, that is, two compounds that are able to be oxidized and form a chromophore that absorbs light at specific wavelengths in relation to the amount of chromophore present. The oxidizing agent formed by the enzyme-catalyzed reaction then reacts with the dye sample to form the chromophore.

Valget av enzymer, det resulterende oksidasjonsmidlet og valget av fargestoffpar varierer sterkt innen området og er for en stor del en funksjon av hvilken analytt som skal bestemmes. For eksempel med bestemmelse av kolesterol i en blodprøve, kan det anvendes et oksidaseenzym, så som kolesteroloksidase. På tilsvarende måte kan etanol eller etanolbestemmelser anvende alkoholoksidase; formaldehydbestemmelser kan anvende aldehydoksidase; eller glyserol-3-fosfatbestemmelser kan anvende glysero-fosfatoksidase. Hydrogenperoksidproduktet fra disse enzymkatalyserte reaksjonene kan videre modifiseres med en etterfølgende enzymkatalysert reaksjon, for å danne et aktivt oksidasjonsmiddel for reaksjon med fargestoffparet for å danne kromoforen. For eksempel kan reaksjonen av hydrogenperoksid for å danne et aktivt oksidasjonsmiddel katalyseres av enzymet pepperrotperoksidase. The choice of enzymes, the resulting oxidizing agent, and the choice of dye pairs varies greatly within the field and is largely a function of the analyte to be determined. For example, with the determination of cholesterol in a blood sample, an oxidase enzyme, such as cholesterol oxidase, can be used. Similarly, ethanol or ethanol determinations may use alcohol oxidase; formaldehyde determinations may use aldehyde oxidase; or glycerol-3-phosphate determinations may use glycero-phosphate oxidase. The hydrogen peroxide product from these enzyme-catalyzed reactions can be further modified by a subsequent enzyme-catalyzed reaction to form an active oxidizing agent for reaction with the dye pair to form the chromophore. For example, the reaction of hydrogen peroxide to form an active oxidizing agent can be catalyzed by the enzyme horseradish peroxidase.

Det er innforstått at læren i henhold til oppfinnelsen har en stor anvendelse, men for den etterfølgende diskusjonen vil analytten bli eksemplifisert av glukose i en væskeprøve av helblod. Det foretrukne kjemiske systemet vil bli eksemplifisert av enzymet glukoseoksidase som virker på glukosesubstratet og danner hydrogenperoksid. Hydrogen-peroksiden vil i sin tur omdannes til aktivt oksidasjonsmiddel ved reaksjonen med et annet enzym, pepperrotperoksidase. It is understood that the teachings of the invention have wide application, but for the following discussion the analyte will be exemplified by glucose in a liquid sample of whole blood. The preferred chemical system would be exemplified by the enzyme glucose oxidase which acts on the glucose substrate to form hydrogen peroxide. The hydrogen peroxide will in turn be converted into an active oxidizing agent by the reaction with another enzyme, horseradish peroxidase.

Hittil har fargestoffet som i sterk grad har blitt brukt i diagnostiske undersøkelser av glukose av den ovenfor beskrevne type, vært kombinasjonen av 3-metyl-2-benzotiazolinonhydrazon, hydrokloridhydrat (MBTH hydrokloirdhydrat) (formel I) sammen med dimetylaminobenzen (formel U). Disse forbindelsene gjennomgår følgende oksidassjons-reaksjon og danner en blåfarget kromofor (formel HI): Hitherto, the dye which has been largely used in diagnostic examinations of glucose of the type described above has been the combination of 3-methyl-2-benzothiazolinone hydrazone, hydrochloride hydrate (MBTH hydrochloride) (formula I) together with dimethylaminobenzene (formula U). These compounds undergo the following oxidation reaction and form a blue colored chromophore (formula HI):

[0] = hydrogenperoksid/pepperrotperoksidase [0] = hydrogen peroxide/horseradish peroxidase

Som beskrevet over, har dette systemet en rekke ulemper. MBTH, selv i hydrokloridhydrat form, er relativt ustabilt under påvirkning av varme og alkalinitet. Videre er reaksjonen over mest effektiv under sterkt sure betingelser, for eksempel pH på 2 eller mindre. Ved disse betingelsene har dessverre enzymene som anvendes i testanordningene, for eksempel glukoseoksidase og pepperrotperoksidase, liten eller ingen aktivitet. Kommersiell praksis har derfor tvunget frem at for å oppnå ct relativt stabilt system, oppnås en optimal pH, for eksempel ca. 4, og det brukes store mengder av både enzymene og fargeparene for å oppveie den reduserte aktiviteten til enzymene og den reduserte effektiviteten ved oksidasjon av koblingsreaksjonen. As described above, this system has a number of disadvantages. MBTH, even in hydrochloride hydrate form, is relatively unstable under the influence of heat and alkalinity. Furthermore, the reaction above is most efficient under strongly acidic conditions, for example pH of 2 or less. Under these conditions, unfortunately, the enzymes used in the test devices, for example glucose oxidase and horseradish peroxidase, have little or no activity. Commercial practice has therefore forced that in order to achieve a relatively stable system, an optimum pH is achieved, for example approx. 4, and large amounts of both the enzymes and the dye pairs are used to compensate for the reduced activity of the enzymes and the reduced efficiency of oxidation of the coupling reaction.

I henhold til foreliggende oppfinnelse, er det nå funnet at det kan tilveiebringes en modifisert form av MBTH som løser stabilitetsproblemet som hittil har vært tilstedeværende, og videre har en effektiv reaktivitet i et miljø som bidrar til aktiviteten til enzymene som anvendes i forsøksanordningene innbefattet her, for eksempel ved pH -verdier i området fra ca. 4 til ca. 7. Dette foretrukne derivat som er meta[3-metyl 2-benzotiazolinon hydrazon]N-sulfonyl benzensulfonat mononatrium, er videre funnet å være meget reaktivt med de ønskede koblingspartnerne, de aromatiske aminer i foreliggende oppfinnelse. According to the present invention, it has now been found that a modified form of MBTH can be provided which solves the stability problem which has hitherto been present, and further has an effective reactivity in an environment which contributes to the activity of the enzymes used in the experimental devices included herein, for example at pH values in the range from approx. 4 to approx. 7. This preferred derivative, which is meta[3-methyl 2-benzothiazolinone hydrazone]N-sulfonyl benzenesulfonate monosodium, is further found to be very reactive with the desired coupling partners, the aromatic amines in the present invention.

MBTH derivatet i henhold til oppfinnelsen kan gjennomgå en oksidativ reaksjon med et stort område av fargeparpartnere, så som aromatiske aminer, fenoler og substituerte fenoler. Videre kan disse reaksjonene skje effektivt ved romtemperatur og ved pH som kan variere fra 4 til 11. I den foretrukne formen av derivatet i henhold til foreliggende oppfinnelse, er oksidasjonsreaksjonen optimal fra pH verdier fra ca. 4 til ca. 7, og er derved spesielt anvendelig i forbindelse med aminfargepartnere av interesse i The MBTH derivative according to the invention can undergo an oxidative reaction with a large range of color pair partners, such as aromatic amines, phenols and substituted phenols. Furthermore, these reactions can take place efficiently at room temperature and at pH which can vary from 4 to 11. In the preferred form of the derivative according to the present invention, the oxidation reaction is optimal from pH values from approx. 4 to approx. 7, and is thereby particularly applicable in connection with amine dye partners of interest i

diagnostisk kjemi, så som 3-dimetylaminobenzosyre og 8-anilino-l-naftalensulfonater. diagnostic chemistry, such as 3-dimethylaminobenzoic acid and 8-anilino-1-naphthalene sulfonates.

I motsetning til MBTH, enten i syrefri eller i syrehydrat form, er dette derivatet bemer-kelsesverdig stabilt, selv ved oppvarming ved 100°C for så mye som 16 timer. Videre, ved betingelsene til oksidasjonsreaksjonen, er de perokside katalyserende enzymer, så som pepperrotperoksidase, spesielt effektive ved å snu oksidasjonskoblingsreaksjonen. Unlike MBTH, either in acid free or in acid hydrate form, this derivative is remarkably stable, even when heated at 100°C for as much as 16 hours. Furthermore, under the conditions of the oxidation reaction, the peroxide catalyzing enzymes, such as horseradish peroxidase, are particularly effective in reversing the oxidation coupling reaction.

Eksempel 1 - Syntese av MBTH derivatet Example 1 - Synthesis of the MBTH derivative

Syntese av meta [3~metyl 2-benzotiazolinonhydrazon] N-sulfony] benzensulfonat mononatrium, [2] Synthesis of meta [3~methyl 2-benzothiazolinone hydrazone] N-sulfony] benzenesulfonate monosodium, [2]

Materiale Material

3-meryi 2-benzotiazolinon hydroklorid (MBTH.HC1), Nal, tetrabutylammonium-hydroksid, metylenklorid og n-metyl-2-pyrrotidon ble innkjøpt fra Aldrich Company, Milwaukee i Wisconsin og brukt uten rensing. Trietylamin ble tilveiebragt fra Baker Chemicals og distribuert av Baxter Company of Phillipsburg, New Jersey. 1,3 disulfonylkloridbenzen ble tilveiebragt fra Fluka Chemicals i Ronkonkoma, New York eller Lancaster Chemicals i Windham, New Hamshire. 3-meryi 2-benzothiazolinone hydrochloride (MBTH.HCl), Nal, tetrabutylammonium hydroxide, methylene chloride and n-methyl-2-pyrrotidone were purchased from the Aldrich Company, Milwaukee, Wisconsin and used without purification. Triethylamine was obtained from Baker Chemicals and distributed by Baxter Company of Phillipsburg, New Jersey. 1,3 disulfonyl chloridebenzene was obtained from Fluka Chemicals in Ronkonkoma, New York or Lancaster Chemicals in Windham, New Hampshire.

Syntese av flj Synthesis of flj

En 4 grams prøve av MBTH.HC1 ble fylt i en 150 ml Erlenmeyerkolbe forsynt med en magnetisk rørstav, og 50 ml n-metyl-2-pyrrolidon og 5 ml trietylamin ble tilsatt. Kolben var lukket med et gummiseptum og plassert på en varmeplate med magnetisk raring. Blandingen ble oppvarmet til 60 - 70°C under kraftig omrøring i 0.5 timer, som ga en gul oppslemming. Kolben ble deretter plassert i isbad for avkjøling. A 4 gram sample of MBTH.HCl was placed in a 150 ml Erlenmeyer flask fitted with a magnetic stir bar, and 50 ml of n-methyl-2-pyrrolidone and 5 ml of triethylamine were added. The flask was closed with a rubber septum and placed on a hot plate with a magnetic stirrer. The mixture was heated to 60-70°C with vigorous stirring for 0.5 hours, which gave a yellow slurry. The flask was then placed in an ice bath for cooling.

En 5 g prøve av 1,3 disulfonylkloridbeti2en ble tilsatt til en 250 ml Erlenmeyerkolbe, forsynt med en magnetisk rørestav. Kolben ble senket ned i isbad og 20 ml n-metyl-2-pyrrolidon ble tilsatt. Blandingen ble rørt inntil alt faststoff var oppløst (ca. 15 minutter). Den MBTH frie baseoppslemmingen, som ble fremstilt tidligere, ble dekantert inn i løsningen. Den resulterende lysgule blandingen fikk reagere ved en isbadtemperatur i 1.5 timer. Etter denne tiden, ble reaksjonen stanset med 10 ml 2N HC1, og ble rørt ytterligere 30 min. ved romtemperatur. 50 mg 12 mesh Norti (aktivert karbonpellets) ble tilsatt i løsningen, og ga en lys gul løsning etter 10 minutters raring. Denne ble deretter filtrert gjennom en fritte med fin grad ved hjelp av en aspirator. Det ble dannet en gul til lys brun glatt løsning. 300 ml 2N HC1 ble tilsatt den rørte gule løsningen, og resulterte i utfelling av et offwhite pulver. Det faste stoffet ble oppsamlet ved hjelp av vakuumfiltrering og produktet ble vasket tre ganger med 25 ml ionebyttet vann. Ved tørking ved 110°C i vakuum i 2 timer ble det erholdt 5.6 g off-white produkt. Produktet ble analysert med<1>H NMR og HPLC og ble funnet å være 97% rent. A 5 g sample of 1,3 disulfonyl chloride betaine was added to a 250 ml Erlenmeyer flask fitted with a magnetic stir bar. The flask was immersed in an ice bath and 20 ml of n-methyl-2-pyrrolidone was added. The mixture was stirred until all solids had dissolved (about 15 minutes). The MBTH free base slurry, which was prepared earlier, was decanted into the solution. The resulting light yellow mixture was allowed to react at an ice bath temperature for 1.5 hours. After this time, the reaction was quenched with 10 mL of 2N HCl and stirred for an additional 30 min. at room temperature. 50 mg of 12 mesh Norti (activated carbon pellets) was added to the solution, giving a light yellow solution after 10 minutes of stirring. This was then filtered through a frit with a fine grade using an aspirator. A yellow to light brown smooth solution was formed. 300 ml of 2N HCl was added to the stirred yellow solution, resulting in the precipitation of an off-white powder. The solid was collected by vacuum filtration and the product was washed three times with 25 mL deionized water. By drying at 110°C in vacuum for 2 hours, 5.6 g of off-white product was obtained. The product was analyzed by<1>H NMR and HPLC and found to be 97% pure.

Forbindelsen [1] er ikke meget løslig i de fleste vanlige organiske løsningsmidler eller vann. Den er imidlertid løslig i basiske løsninger og polare løsningsmidler, så som DMSO, NMP og DMF. The compound [1] is not very soluble in most common organic solvents or water. However, it is soluble in basic solutions and polar solvents such as DMSO, NMP and DMF.

Syntese av [ 2] Synthesis of [ 2]

En 2.0 g prøve av råstoffet [1] ble oppløst i 50 ml metylenklorid. 4 ml IM tetrabutyl-ammoniumhydroksid ble tilsatt sakte, i løpet av 2 minutter, til den omrørte suspensjonen, og ga en lys gul løsning. Løsningen ble deretter vasket med 10 ml ionebyttet vann og tørket over vannfritt natriumsulfat. Sulfatet ble fjernet via gravitasjonsfjltrering, og den resulterende blandingen ble inndampet til tørrhet med en rotavapor. Det ble oppsamlet en tykk, gul olje. Oljen ble tatt opp med 125 mi aceton og 10 ml 20% Nal i aceton ble tilsatt i løpet av 5 minutter. Det kom til syne en hvit utfelling. Blandingen fikk reagere i ytterligere 20 minutter og bunnfallet ble oppsamlet via vakuumfiltrering med en fritte med fin-grad. Resulterende offwhite faste stoffer ble vasket tre ganger med 20 ml aceton. Ved tørking ved 110°C i 45 min., ble det erholdt 1.3 g (65%) av det ønskede produktet. A 2.0 g sample of the raw material [1] was dissolved in 50 ml of methylene chloride. 4 mL of 1M tetrabutylammonium hydroxide was added slowly, over 2 minutes, to the stirred suspension, giving a pale yellow solution. The solution was then washed with 10 ml of deionized water and dried over anhydrous sodium sulfate. The sulfate was removed via gravity filtration, and the resulting mixture was evaporated to dryness with a rotavapor. A thick, yellow oil was collected. The oil was taken up with 125 ml of acetone and 10 ml of 20% Nal in acetone was added over 5 minutes. A white precipitate appeared. The mixture was allowed to react for a further 20 minutes and the precipitate was collected via vacuum filtration with a fine grade frit. Resulting off-white solids were washed three times with 20 mL of acetone. By drying at 110°C for 45 min., 1.3 g (65%) of the desired product was obtained.

Forbindelsen [2] er meget løslig i vann og i en vann-alkoholblanding. Det faste stoffet er stabilt i luft og lys, men løsningen av denne dekomponerer sakte til en lysgul, uklar blanding når den utsettes for lys i lang tid. The compound [2] is very soluble in water and in a water-alcohol mixture. The solid is stable in air and light, but its solution slowly decomposes to a pale yellow, cloudy mixture when exposed to light for a long time.

EKSEMPEL 2 EXAMPLE 2

Fremstilling av en testanordning Manufacture of a test device

En remse av polymermembran (reaksjonsmatriks) dyppes i den vandige løsningen i tabell 1 inntil metning. Den fjernes fra løsningen og overskuddsreagens klemmes av med en glasstang. Remsen henges deretter i sirkulerende luft ved 56°C i 5-10 minutter for tørking, hvoretter remsen fjernes og dyppes i den organiske løsningen beskrevet i tabell 1 inntil meining. Den tørkes igjen som i det tidligere trinnet. Den resulterende remsen har en ønsket form for testing. A strip of polymer membrane (reaction matrix) is dipped in the aqueous solution in table 1 until saturation. It is removed from the solution and excess reagent is squeezed off with a glass rod. The strip is then hung in circulating air at 56°C for 5-10 minutes for drying, after which the strip is removed and dipped in the organic solution described in Table 1 until it is dissolved. It is dried again as in the previous step. The resulting strip has a desired shape for testing.

EKSEMPEL 3 - Bestemmelse av glukose EXAMPLE 3 - Determination of glucose

En glukoseholdig blodprøve påføres på overflaten av den reagensimpregnerte remsen. Prøven absorberes umiddelbart i matriksen og det kommer til syne en blå farge. Intensiteten til fargen øker med tiden og er proporsjonal med konsentrasjonen av analytten. Basert på fargeintensiteten, bestemmes gtukosekonsentrasjonen ved sammen-ligning med en standardkalibreringskurve. På samme måte danner en vandig løsning av hydrogenperoksid (organiske perokstder, ferri og kinon) også den ønskede blåfargen på den reagensimpregnerte remsen. Konsentrasjonen av analytten kan bestemmes på samme måte som over. A glucose-containing blood sample is applied to the surface of the reagent-impregnated strip. The sample is immediately absorbed into the matrix and a blue color appears. The intensity of the color increases with time and is proportional to the concentration of the analyte. Based on the color intensity, the glucose concentration is determined by comparison with a standard calibration curve. In the same way, an aqueous solution of hydrogen peroxide (organic peroxides, ferric and quinone) also forms the desired blue color on the reagent-impregnated strip. The concentration of the analyte can be determined in the same way as above.

Claims (6)

1. Forsøksanordning inneholdende et reagenssystem for bestemmelse av nærværet eller mengden av en analytt i en prøve, hvor reagenssystemet innbefatter enzymer for å danne et oksydasjonsmiddel i mengder som er indikative for mengdene av analytt i prøven, der reagenssystemet innbefatter et fargepar som danner en kromofor ved oksydasjon med oksydasjonsmidlet, karakterisert ved at fargeparet omfatter: meta[3-metyl 2-benzotiazolinon hydrazon]N-sulfonyl benzensulfonat mononatrium.1. Test device containing a reagent system for determining the presence or amount of an analyte in a sample, wherein the reagent system includes enzymes to form an oxidizing agent in amounts indicative of the amounts of analyte in the sample, wherein the reagent system includes a color pair that forms a chromophore upon oxidation with the oxidizing agent, characterized in that the color pair comprises: meta[3-methyl 2-benzothiazolinone hydrazone]N-sulfonyl benzenesulfonate monosodium. 2. Forsøksanordning i henhold til krav 1, karakterisert v e d at enzymene er valgt fra gruppen bestående av glukoseoksidase, kolesteroloksidase, alkoholoksidase, urikase, aldehydoksidase og glyserifosfatoksidase.2. Experimental device according to claim 1, characterized in that the enzymes are selected from the group consisting of glucose oxidase, cholesterol oxidase, alcohol oxidase, uricase, aldehyde oxidase and glyceryl phosphate oxidase. 3. Forsøksanordning i henhold til krav 2, karakterisert ved at enzymene videre innbefatter peroksidase eller uorganisk kompleks med peroksidaselignende egenskaper.3. Test device according to claim 2, characterized in that the enzymes further include peroxidase or inorganic complex with peroxidase-like properties. 4. Forsøksanordning i henhold til krav 2, karakterisert ved at enzymene innbefatter glukoseoksidase og pepperrotperoksydase.4. Experimental device according to claim 2, characterized in that the enzymes include glucose oxidase and horseradish peroxidase. 5. Forsøksanordning i henhold til krav 1, karakterisert ved at fargeparet videre innbefatter 3-dimetylaminobenzosyre.5. Test device according to claim 1, characterized in that the color pair further includes 3-dimethylaminobenzoic acid. 6. Forsøksanordning i henhold til krav 1, karakterisert ved at fargeparet videre innbefatter 8-anilino-l-natfalensulfonat.6. Experimental device according to claim 1, characterized in that the color pair further includes 8-anilino-1-naphthalene sulfonate.
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